Most nanomedicines that attack tumors by Reactive Oxygen Species (ROS) based on lipid peroxidation mechanisms require external activation to work. The leading example is Photodynamic Therapy (PDT), for which an external light source stimulates ROS production. PDT has been utilized in the treatment of melanoma patients as part of palliative care, and it has shown promise in clinical trials. However, it has several limitations in terms of practical applications, such as inadequate photosensitizer (PS) dispersion, tumor-oxygenation dependency, and therapeutic escape in aggressive tumors. To overcome these obstacles, our targeted dual-modal PDT/Chemodynamic therapy (CDT) has produced promising results, with a stronger therapeutic impact than CDT or PDT alone. We herein report polymer nanoparticles functionalized with endothelin ligands (EDN3-CP nanocomposite) that are specifically designed to target melanoma tumors. The nanoparticles are intrinsically active against melanoma tumor cells even without the use of external light. The Iron in the EDN3-CP nanocomposite catalyzes the Fenton reaction in tumor cells, allowing for CDT. CDT produces ROS by converting endogenous hydrogen peroxide (H₂O₂), which is elevated in most tumor microenvironments (TME), to hydroxyl radicals (˙OH). The ˙OH that result can quickly oxidize bio-macromolecules, destroy DNA and kill tumor cells. The EDN3-CP nanocomposite is therefore not reliant on oxygen availability, making it a promising therapeutic option for hypoxic malignancies. Herein, the melanoma-targeted EDN3-CP nanocomposite demonstrated substantial PDT and CDT together with respect to Malme-3M and A375 melanoma cells. Our findings suggest that tumor cells that overexpress EDNRB, particularly melanoma cells, can be effectively targeted. Our data indicate that the EDN3-CP nanocomposite allows for ferroptosis-assisted CDT, paving the way to combine with PDT for maximized therapeutic efficacy as a new therapeutic approach to tumor treatment.

中文翻译：

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基于共轭聚合物纳米粒子的内皮素轴联合化学动力-光动力治疗多功能系统

大多数通过基于脂质过氧化机制的活性氧 (ROS) 攻击肿瘤的纳米药物需要外部激活才能发挥作用。领先的例子是光动力疗法 (PDT)，外部光源刺激 ROS 的产生。PDT 已被用于治疗黑色素瘤患者，作为姑息治疗的一部分，并在临床试验中显示出前景。然而，它在实际应用方面有一些局限性，例如光敏剂 (PS) 分散不足、肿瘤氧合依赖性和侵袭性肿瘤的治疗逃逸。为了克服这些障碍，我们的靶向双模式 PDT/化学动力学疗法 (CDT) 产生了可喜的结果，比单独的 CDT 或 PDT 具有更强的治疗效果。我们在此报告了专门设计用于靶向黑色素瘤肿瘤的内皮素配体（EDN3-CP 纳米复合材料）功能化的聚合物纳米颗粒。即使不使用外部光，纳米颗粒也对黑色素瘤肿瘤细胞具有内在活性。EDN3-CP 纳米复合材料中的铁催化肿瘤细胞中的芬顿反应，从而产生 CDT。CDT 通过转化内源性过氧化氢 (H₂ O ₂ )，在大多数肿瘤微环境 (TME) 中被提升为羟基自由基 (˙OH)。产生的˙OH能迅速氧化生物大分子，破坏DNA，杀死肿瘤细胞。因此，EDN3-CP 纳米复合材料不依赖于氧气的可用性，使其成为缺氧恶性肿瘤的一个有前途的治疗选择。在此，针对 Malme-3M 和 A375 黑色素瘤细胞的黑色素瘤靶向 EDN3-CP 纳米复合材料证明了大量的 PDT 和 CDT。我们的研究结果表明，可以有效靶向过度表达 EDNRB 的肿瘤细胞，尤其是黑色素瘤细胞。我们的数据表明，EDN3-CP 纳米复合材料允许铁死亡辅助 CDT，为与 PDT 结合作为一种新的肿瘤治疗方法最大限度地提高治疗效果铺平了道路。